tbuckley/cabot-search huggingface dataset:
Influence of albumin and methotrexate clearance on high-dose methotrexate-induced mucositis.
Authors: Zachary L. Taylor, Tamara P. Miller, Nicholas DeGroote, Lauren Pommert, Oluwafunbi Awoniyi, Sarah Board, Ethan Poweleit, Samuel Kastner, Ngozi Ugboh, Vivek Joshi, Nicholas Ambrosino, Allison Weisnicht, Heidi Hsiao, Brooke Bernhardt, Eric Scott Schafer, Maureen Megan O'Brien, Sharon M. Castellino, Laura Ramsey
Journal: Journal of Clinical Oncology (2022)

e15081 Background: Methotrexate (MTX) is a cornerstone of therapy for several types of cancer. HDMTX-induced mucositis can impact quality of life and delay subsequent chemotherapy. Objective: The objective of this study was to understand the factors increasing risk for mucositis in patients receiving HDMTX in a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric and young adult patients ages 0-32 years at diagnosis who received at least one dose of HDMTX (&gt;500 mg/m 2 ) at Children’s Healthcare of Atlanta or Cincinnati Children’s Hospital Medical Center from January 2010 through December 2020. Demographic and clinical variables were manually abstracted, while medications and lab values were electronically pulled from the electronic medical record. Common Terminology Criteria for Adverse Events v5 was used to identify the presence and grade of mucositis after HDMTX administration. Institutional review board approval was obtained at each site. Chi-square and t-tests, as appropriate, were calculated using GraphPad Prism v9. MTX concentrations were fit to a published pharmacokinetic model to estimate clearance using NONMEM. Results: The cohort is described in Table. The rate of mucositis was highest after the first HDMTX administration (54.6%), when the MTX clearance is slowest (30.1%&lt;10 L/hr/1.73m 2 and albumin was lowest (14.3%&lt;2.5g/dL). Mucositis was significantly more likely in patients with hypoalbuminemia and in patients with MTX clearance &lt;10 L/hr/1.73m 2 (OR 1.75 (CI: 1.503 to 2.028), p&lt;0.0001 and OR 1.43 (CI: 1.236 to 1.653), p&lt;0.0001, respectively). Conclusions: Mucositis after administration of HDMTX is common, with 72% of patients experiencing at least grade 1 mucositis and a third of HDMTX administrations leading to mucositis. Chart abstraction is ongoing at a third hospital to increase the sample size, particularly those of Hispanic/Latino ethnicity, in order to investigate differences by race and ethnicity. In addition, current analyses are evaluating the impact of changes in supportive care on HDMTX-induced mucositis and other adverse events. The results of this study will demonstrate who is at highest risk for adverse events so supportive care can be tailored during this potentially toxic chemotherapy.[Table: see text]
Update of a phase II, multicenter clinical trial: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Jin Yan, Yunwei Han, Li Zhang, Yongdong Jin, Hao Sun
Journal: Journal of Clinical Oncology (2022)

e15566 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients. Methods: In this open label, single-arm, multi-center, phase II clinical trial, 29 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m 2 , po, d1-14, q3w) and oxaliplatin (130 mg/m 2 , iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (January 18, 2022), the total 29 patients were enrolled, of which 23 patients were available for efficacy assessment. In best overall response assessment, there were 56.5% PR (13/23), 34.8% SD (8/23) and 8.7% PD (2/23). The ORR was 56.5% (95% CI, 34.5-76.8%) and DCR was 91.3% (95% CI, 72.0-98.9%). The longest duration of treatment was 17.5 months. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥30%) were hypertension, leukopenia, nausea/vomiting, hypertriglyceridemia, neutropenia, hypohemoglobinemia, hypoalbuminemia. Grade 3/4 TRAEs (≥10%) were neutropenia (13.8%), hypertension (13.8%) and hypertriglyceridemia (10.3%). One grade 5 TRAE was pancytopenia that occurred at 2.7 months. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed favorable anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in randomized study continued subsequently. Clinical trial information: ChiCTR1900028417.
Basket study of oral progesterone antagonist onapristone extended release (ONA-XR) in progesterone receptor positive (PR+) recurrent granulosa cell (GCT), low-grade serous ovarian (LGSOC), or endometrioid endometrial cancer (EEC).
Authors: Rachel N. Grisham, Karen Li, Qin Zhou, Alexia Iasonos, Jeffrey Girshman, Pooja Shah, Dasom Jang, Chrisann Kyi, Seth M. Cohen, Roisin Eilish O'Cearbhaill, Claire Frances Friedman, Vicky Makker, Paul Sabbatini, Martee Leigh Hensley, Dmitriy Zamarin, Carol Aghajanian
Journal: Journal of Clinical Oncology (2022)

5521 Background: ONA-XR is a type I full progesterone antagonist that inhibits progesterone-mediated PR activation and stabilizes PR association with corepressors. GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers that generally have poor responses to chemotherapy. Methods: This is an open-label, single-institution basket study of ONA-XR in patients with PR+ recurrent GCT (cohort 1), LGSOC (cohort 2), or EEC (cohort 3) (NCT03909152). Eligible patients required receipt of &gt;1 prior line of chemotherapy, measurable disease by RECIST 1.1, and tumor tissue collected ≤3 years prior to enrollment with PR ≥ 1% by IHC. Patients received ONA-XR 50 mg PO BID until progression or intolerable toxicity. The study was designed as 3 parallel Simon 2-Stage studies. The primary objective was to evaluate efficacy, determined by RECIST 1.1, with at least 1/14 (cohort 1), 2/16 (cohort 2) or 4/19 (cohort 3) responses needed during stage 1 for advancement to stage 2. Secondary objectives included safety and tolerability, clinical benefit rate (CBR; stable disease lasting ≥ 16 weeks), and progression-free survival (PFS) as estimated by Kaplan Meier method. Results: The study enrolled patients to cohorts 1-3 from 5/2019 to 5/2020. Cohort 2 (LGSOC) enrolled 5 patients and cohort 3 (EEC) enrolled 1, both closed early due to slow accrual. Cohort 1 (GCT) enrolled 14 patients and completed Stage 1 accrual. There were no responses by RECIST 1.1 criteria observed in cohorts 1-3. In cohort 2 (LGSOC), 4/5 enrolled patients were evaluable, the median PFS was 4.4 months (1.8-NE) and CBR was 50% (6.8-93.2%). All 14 patients enrolled to cohort 1 (GCT) were evaluable with a median PFS of 3.5 months (1.6-8.8%), 6-month PFS rate of 30.1 % (8.4-56%), and 12-month PFS rate of 20.1% (3.5-46.4%). The CBR was 35.7% (12.8-64.9%). Two patients with GCT remain on active treatment for &gt; 18 months. Grade 3 adverse events occurred in 5 patients: abdominal pain (2), small bowel obstruction (1), syncope (1), thromboembolism (1), urinary tract infection (1), and febrile neutropenia (1). Grade 3 laboratory toxicity occurred in 5 patients: anemia (2), neutropenia (1) and lymphopenia (2). Conclusions: ONA-XR was well tolerated and exhibited a 12-month PFS rate of 20.1% and a CBR of 35.7% in patients with GCT. No objective responses were observed. Cohorts 1-3 have closed to accrual, with 2 patients continuing active treatment for &gt;18 months. Cohort 4, which combines ONA-XR with anastrozole, is currently enrolling patients with GCT. Clinical trial information: NCT03909152. [Table: see text]
KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer.
Authors: Hope S. Rugo, Joohyuk Sohn, Yolanda Jerez Gilarranz, Lucia Gonzalez-Cortijo, Amir Sonnenblick, Dhanusha Sabanathan, Ernesto Pablo Korbenfeld, Daniel Egle, Brigitte Poirier, Flora Zagouri, Alexios Matikas, Sercan Aksoy, Umut Demirci, Pier Ramos-Elias, Seock-Ah Im, Fatima Cardoso, Liyi Jia, Carlos Baccan, Konstantinos Tryfonidis, Peter Schmid
Journal: Journal of Clinical Oncology (2022)

TPS1118 Background: HR+/HER2− advanced breast cancer that progresses on endocrine therapy is treated with chemotherapy (chemo). The phase 1b KEYNOTE-028 trial showed durable activity with pembrolizumab (pembro) monotherapy in previously treated HR+/HER2−, PD-L1–positive (combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study of pembro + chemo vs placebo (pbo) + chemo in centrally assessed PD-L1–positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer (mBC) after progression on prior endocrine therapy. Methods: ∼800 patients (pts) with HR+/HER2− locally recurrent inoperable or mBC who are candidates for chemo (no prior chemo for metastatic disease) with PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line with CDK4/6 inhibitor treatment for mBC in pts who had a relapse within 24 mo of primary surgery. Pts without prior CDK4/6 inhibitor treatment may enroll if they had progressed within 6 mo of starting endocrine therapy for metastatic disease and had previously relapsed within 24 mo of primary tumor surgery while on adjuvant endocrine therapy. Pts are randomized 1:1 to receive pembro 200 mg IV or pbo Q3W, each in combination with investigator’s choice of chemo: paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m 2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m 2 IV on day 1 Q4W; or capecitabine 1000 mg/m 2 PO BID on days 1–14 Q3W. Randomization is stratified by tumor PD-L1 (CPS 1–9 vs ≥10), presence of visceral metastases (yes vs no), and chemo on-study (taxanes vs liposomal doxorubicin vs capecitabine). Treatment is continued until disease progression, unacceptable toxicity, withdrawal, or, for pembro/pbo, completion of 35 cycles (̃2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed Q9W for 54 wk and then Q12W thereafter. AEs occurring from randomization until 30 d after treatment discontinuation (90 d for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by BICR and OS in pts with PD-L1 CPS ≥10 and ≥1 tumors, separately. Enrollment is ongoing at 204 international sites. Clinical trial information: NCT04895358.
Ultra-deep sequencing with unique molecular identifier(UMI) for detection of ctDNA by fragment profiling using machine learning.
Authors: Hu Yukai, Hu Nan, Liao Rui, Wang Bing, Duan Xiaohong, Yang Chunyan, Wang Lifen, Qianhui Wan, Zhihua Pei, Zhou Qiming, Dongliang Wang
Journal: Journal of Clinical Oncology (2022)

e15508 Background: Liquid biopsy has been well known for its potential in cancer detection, non-invasive tumor genotyping and disease surveillance. However, ctDNA levels are low in the early stages of monitoring and postoperative progression of most tumors, which makes detection and analysis of ctDNA quite complicated. Methods: In our study, fixed-sequence UMI double-ended sequencing with a 1123-gene panel was used both on blood samples from 200 healthy donors and tissue-plasma samples from 1000 colorectal cancer (CRC) patients. First, GATK mutation detection was performed on tissue and plasma samples from 700 CRC patients to obtain trustable positive mutation sites in DBSNP138 database, meanwhile Samtools MPileUP analysis was performed on 200 healthy samples to obtain negative sites at low frequencies below 1%. Then, six features were extracted from the supporting variation sequences for the two above types of loci: IS (insert size), VBQ (variation base quality), MRBQ (mean read base quality), PIR (position in read), MQ (mapping quality) and R1&amp;R2 (read 1 and read 2 of the paired-end sequencing). All the above data were used to establish the training set model; after that, SNV background noise was modeled by SVM and optimized through five-fold cross-validation. Last, plasma samples from 300 CRC patients were used as a validation set to verify the accuracy of the model. Results: The test set of 300 CRC patients was used to verify the accuracy of the model, in which， the effectiveness of VAF mutation frequency above 0.2% was 95%, and above 0.02% was 80% in plasma. Conclusions: We established a specific method based on UMI two-terminal capture with machine learning modeling, which was significantly superior to any available method in eliminating noise background errors and filtering false-positive low-frequency mutation.
Ocular toxicities associated with anticancer therapies: Are we missing something in the blind spot?
Authors: Bhawana Awasthy, Arun Maseeh, Prabhati Mukherji
Journal: Journal of Clinical Oncology (2022)

e15001 Background: Ocular toxicities are common challenges associated with anticancer agents, including small molecules, antibody-drug conjugates (ADC), targeted antibodies, particularly those targeting Epidermal Growth Factor Receptor (EGFR), Mitogen-activated protein kinase (MEK) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). This subject suffers from a paucity of consensus guidelines, especially drug class versus severity of toxicity versus ocular anatomy. The aim of this paper is to examine the ocular side effects of various classes of anticancer therapies. Methods: Approved anticancer drugs known to be associated with ocular toxicity were reviewed as of Dec-2021. US FDA Labels were reviewed, as were further publications on said drugs. Ocular toxicities were then classified based on the anatomy of the eye, class of drug and drug target, severity and the recommended surveillance and management. Results: The most common ocular toxicities were mild including “visual disturbances” and conjunctivitis. Severe toxicities were reported as well, including corneal ulceration, retinal vascular occlusion, optic neuritis, and even cortical blindness. Our review clearly indicates that each class of drugs has a distinct ocular toxicity pattern, including the precise segment of the eye involved, severity and pattern of manifestation. Drug related toxicity involving the anterior segment tends to be of lesser severity, whereas posterior segment toxicity is more severe, and, as such, may result in treatment interruptions. Molecular-pathway-specific toxicity patterns were noted. EGFR inhibitors were associated with corneal-ulceration and microcysts. MEK inhibitor-associated retinopathy (MEKAR) is documented, and drugs (e.g. Trametinib) increase the risk of retinal detachment and retinal vascular occlusion. We noted a pattern of Monoclonal Antibodies (e.g. Cetuximab) having lower adverse events than the small molecule (e.g. Gefitinib) having the similar pathway of action. ADCs (12 US FDA approved) are known to affect various ocular tissues, commonly involving the ocular surface, with intra-class differences. Conclusions: Our review highlights the need for an ophthalmic referral at baseline, prior to initiating anticancer drugs known to cause ocular toxicities. Cancer patients need consensus-based multidisciplinary global standardized algorithms for surveillance, early diagnosis and management of ocular toxicities associated with anticancer therapies.
Prevalence of DNA damage repair (DDR) alterations in patients with metastatic hormone-sensitive prostate cancer (mHSPC) receiving enzalutamide (ENZA) or placebo (PBO) plus androgen deprivation therapy (ADT): ARCHES post hoc analysis.
Authors: Arun Azad, Taro Iguchi, Boris Alekseev, Neal D. Shore, Jennifer Sugg, Gabriel P. Haas, Michele Wozniak, Thomas O'Brien, Douglas Laird, Arnulf Stenzl, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2022)

5074 Background: DDR alterations are associated with poorer prognosis, including shorter overall survival (OS), in patients with mHSPC. In ARCHES (NCT02677896), patients with mHSPC treated with ENZA + ADT had a reduced risk of radiographic progression or death and improved OS versus PBO + ADT. This post hoc analysis assessed the prevalence of DDR alterations and associated baseline characteristics in patients with mHSPC in ARCHES. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. Germline DDR alteration testing was performed in blood using Ambry Genetics CustomNext-Cancer panel; 16 DDR-related genes were reported in the subset of patients who consented to participate in a pharmacogenomic study (n=664; Table). Descriptive analyses of baseline demographics and disease characteristics by DDR status were performed. Results: Of 664 patient samples tested, 652 were evaluable for analysis (ENZA + ADT, n=326; PBO + ADT, n=326). Baseline characteristics of these patients were similar to the ARCHES intent-to-treat population. The prevalence of DDR+ patients was lower than expected (n=34/652, 5.2%; Table). Of DDR+ patients, 13 (38.2%) had low-volume disease, compared with 228 (36.9%) of DDR− patients. High-volume disease was present in 21 (61.8%) DDR+ and 390 (63.1%) DDR− patients. Of DDR+ patients, 6 (17.6%) had localized disease at initial diagnosis (M0), compared with 145 (23.5%) DDR− patients. De novo metastatic disease at initial diagnosis (M1) was present in 28 (82.4%) DDR+ patients and 465 (75.2%) DDR− patients. Of DDR+ patients, 29 (85.3%) were from Europe, four (11.8%) were from North America, and one (2.9%) was from the Asia-Pacific region. Conclusions: This post hoc analysis found a lower prevalence of DDR alterations in patients with mHSPC in ARCHES, compared with the 7–12% previously reported in patients with metastatic castration-resistant prostate cancer (Lozano et al. Br J Cancer 2021; Pritchard et al. N Engl J Med 2016). We did not identify differences in baseline disease characteristics based on DDR status. Clinical trial information: NCT02677896. [Table: see text]
Integration of traditional molecular diagnostic tools and targeted next generation sequencing for the precise diagnosis and management of adult gliomas.
Authors: Duaa Kanan, Şebnem Safı, Tarek Kanan, Serkan Celik, Bala Başak Öven, Ozlem Yapicier
Journal: Journal of Clinical Oncology (2022)

e14011 Background: It is known that gliomas represent a wide variety of entities with varying biological features and clinical outcomes (Neuropathol Exp Neurol 2019, 78). Hence, optimal tumor classification that aids in the diagnosis and management of patients and which supports the use of specific treatment modalities is of critical importance in neuro-oncology. Targeted next-generation sequencing (NGS) has proven to be an efficient and reliable tool for identifying prognostic biomarkers for the diagnosis of CNS tumors (Neurooncol Adv 2020, 2). Here, an analysis of the impact of using NGS in addition to traditional molecular tools on tumor classification and therapy selection was analyzed; and the overall concordance was evaluated. Methods: Patients with glial tumors who were seen at our clinic between 2019-2020 and had an NGS analysis in addition to traditional molecular studies were included. All clinical data, histopathological findings and genetic reports were retrieved from the electronic medical record. We retrospectively studied each of the patients’ findings with regards to their clinical diagnosis, grade, anatomic localization; ki67 (%); TP53, IDH and ATRX mutations; as well as microsatellite instability (MSI) and additional mutational studies such as HER2 and BRAF for some patients. The concordance between the genetic and molecular data regarding TP53 and IDH mutations was also analyzed. Results: 9 patients (66.7% male) with grade 3-4 gliomas were identified at our single-center oncology institution. Most patients had a diagnosis of glioblastoma (55.6%), with a median age of 43 years at the time of diagnosis. 22.2% (2/9) had a genetic analysis through FoundationOneCDx. The concordance of the identification of mutations by NGS and immunohistochemistry (IHC) was 77.8% (7/9) for IDH mutations, and 55.6% (5/9) for TP53 mutations. NGS led to the identification of TP53 mutation in 1 patient (11%) which IHC failed to show. NGS also supported the use of targeted therapy [dabrafenib] in 1 patient (11.1%) with BRAF positivity. Conclusions: Traditional molecular diagnostic tools and targeted NGS are not perfectly concordant, but when integrated together can lead to a more comprehensive identification of genetic mutations and potential biomarkers. This can have significant implications on the precise diagnosis and potential use of targeted therapies of adult gliomas in the future.